Post on 29-Jul-2020
Glycogen Metabolism
BCH 340 lecture 9
Glycogen is homopolysaccharide formed of branched D-glucose
units
The primary glycosidic bond is 1-4-linkage
Each branch is made of 6-12 glucose units. At the branching
point, the chain is attached by 1-6 linkage
Structure of glycogen
Glucose is stored as glycogen predominantly in liver and
muscle cells.
Liver glycogen is about 120 grams (about 6 % of liver
weight).
Muscle glycogen is about 350 grams (about 1 % of
total muscles weight).
Location of glycogen
Liver glycogen: It maintains normal blood glucose
concentration especially during the early stage of fast
(between meals). After 12-18 hours fasting, liver glycogen is
depleted.
Muscle glycogen: It acts as a source of energy within the
muscle itself especially during muscle contractions.
Functions of glycogen
Glycogenesis: It is the formation of glycogen in liver andmuscles
Substrates for glycogen synthesis:
1. In liver:
o Blood glucose
o Other hexoses: fructose and galactose
o Non-carbohydrate sources: (gluconeogenesis) e.g.lactic acid, glycerol and lactate. These are convertedfirst to glucose, then to glycogen
2. In muscles:
o Blood glucose only
OO
OHOH
HH
H
CH2
H
HN
N
O
O
OP
O
O
P
O
O
H O
OH
H
OHH
OH
CH2OH
H
O
H
O
P
O
O
H O
OH
H
OHH
OH
CH2OH
H
O
H
OO
OHOH
HH
H
CH2
H
HN
N
O
O
OP
O
O
P
O
O
OPO
O
O
PPi
+
UDP-glucose
glucose-1-phosphate UTP
UDP-Glucose Pyrophosphorylase
Uridine diphosphate glucose (UDP-glucose) is the
immediate precursor for glycogen synthesis
OO
OHOH
HH
H
CH2
H
HN
N
O
O
OP
O
O
P
O
O
H O
OH
H
OHH
OH
CH2OH
H
O
H
O
P
O
O
H O
OH
H
OHH
OH
CH2OH
H
O
H
OO
OHOH
HH
H
CH2
H
HN
N
O
O
OP
O
O
P
O
O
OPO
O
O
PPi
+
UDP-glucose
glucose-1-phosphate UTP
UDP-Glucose Pyrophosphorylase
UDP-glucose is formed from glucose-1-phosphate:
glucose-1-phosphate + UTP UDP-glucose + 2 Pi
Cleavage of PPi is the only energy cost for glycogen
synthesis
H O
OH
H
OHH
OH
CH2OH
H
O H
H
OHH
OH
CH2OH
H
O
HHC
CH
NH
CH2
O
O
H O
OH
H
OHH
OH
CH2OH
HH
C
CH
NH
CH2
O
O1
5
4
3 2
6
H O
OH
H
OHH
OH
CH2OH
HH
O1
5
4
3 2
6
P O P O Uridine
O
O
O
O
C
CH
NH
CH2
HO
O
tyrosine residue of Glycogenin
O-linked glucose residue
+ UDP
UDP-glucose
Glycogenin (dimer) initiates glycogen synthesis
Glycogenin is an enzyme that catalyzes attachment of a glucose molecule to one of its own tyrosine residues.
UDP is released as a product
Glycogenin then catalyzes glucosylation at C4 of the attached
glucose (UDP-glucose again the donor), to yield an O-linked
disaccharide with α(14) glycosidic linkage
This is repeated until a short linear glucose polymer (glycogen
primer) with α(14) glycosidic linkages is built up
on Glycogenin
H O
OH
H
OHH
OH
CH2OH
H
O H
H
OHH
OH
CH2OH
H
O
HHC
CH
NH
CH2
O
O
H O
OH
H
OHH
OH
CH2OH
HH
C
CH
NH
CH2
O
O1
5
4
3 2
6
H O
OH
H
OHH
OH
CH2OH
HH
O1
5
4
3 2
6
P O P O Uridine
O
O
O
O
C
CH
NH
CH2
HO
O
UDP-glucose
O-linked glucose residue
(14) linkage
+ UDP
+ UDP
Glycogen Synthase then catalyzes
elongation of glycogen chains initiated by
Glycogenin.
By the action of Glycogen Synthase (key enzyme of
glycogenesis) UDP-G molecules are added to glycogen
primer causing elongation of the α1-4, branches up to 11
glucose units.
glycogen(n residues) + UDP-glucose glycogen(n +1 residues) + UDP
A branching enzyme transfers a segment (minimum 6 Glc
residues) from the end of a glycogen chain to the C6
hydroxyl of a glucose residue of glycogen to yield a
branch with an α(16) linkage. The new branches are
elongated by the glycogen synthase and the process is
repeated.
Glycogen catabolismIt is the breakdown of glycogen into glucose
(in liver) and lactic acid (in muscles)
Two major enzymes participate in all glycogen degradation:
Glycogen phosphorylase
and
Glycogen debranching enzyme
Glycogen Phosphorylase (the key enzyme of glycogenolysis)
catalyzes phosphorolytic cleavage (addition of Pi) of the α(14)
glycosidic linkages of glycogen, releasing glucose-1-phosphate as
reaction product
glycogen(n residues) + Pi glycogen (n–1 residues) + glucose-1-phosphate
Always acts at nonreducing end, stops at fourth
glucose from α 1,6 branch point
Debranching enzyme has 2 independent active sites,
consisting of residues in different segments of a single
polypeptide chain:
1. The transferase
2. The α (16) glucosidase
The transferase transfers 3 glucose residues from a 4-residue limit branch to the end of another branch, diminishing
the limit branch to a single glucose residue.
The α(16) glucosidase
moiety of the debranching
enzyme then catalyzes
hydrolysis of the α(16)
Linkage by adding H2O, yielding free glucose
This is a minor fraction of glucose released from glycogen
The major product of glycogen breakdown is
glucose-1-phosphate, from Phosphorylase activity.
Glucose-1-P formed by phosphorolytic cleavage of
glycogen is converted into glucose-6-P by
Phosphoglucomutase (catalyzes the reversible reaction):
glucose-1-phosphate glucose-6-phosphate
• Glucose 6-phosphate derived from glycogen can be:
o used as a fuel for anaerobic or aerobic metabolism as in, for instance, muscle;
o converted into free glucose in the liver and subsequently released into the blood to maintain a relatively level of blood glucose;
o processed by the pentose phosphate pathway to generate NADPH or ribose in a variety of tissues
Regulation of Glycogen Metabolism
Glycogen reserves are the most immediately available
large source of metabolic energy for mammals
Storage and utilization are under dietary and
hormonal control
Glycogen synthase and glycogen phosphorylase are
the targets of allosteric modulators and of covalent,
reversible modification (phosphorylation)
Allosteric regulation of phosphorylase activity
Glycogen Phosphorylase in muscle is subject to allostericregulation by AMP, ATP, and glucose-6-phosphate. A separate isozyme of Phosphorylase expressed in liver is less sensitive to these allosteric controls
o AMP (present significantly when ATP is depleted) activates Phosphorylase
o ATP & glucose-6-phosphate inhibit Phosphorylase
Thus glycogen breakdown is inhibited when ATP and glucose-6-phosphate are plentiful
Glycogen Synthase is allosterically activated by glucose-6-phosphate (opposite of the effect on Phosphorylase)
Thus, glycogen synthesis is activated when glucose-6-phosphate is plentiful
These controls benefit the cell because it is more useful to a cell to store glucose as glycogen when the input to Glycolysis (glucose-6-P), and the main product of Glycolysis (ATP), are adequate.
Primary hormones :
1. epinephrine (adrenaline)
2. glucagon
3. insulin
The actions of these hormones on glycogen phosphorylase and glycogen synthase are indirect
Regulation by covalent modification
(phosphorylation)
Glucagon
Low levels of glucose induce release of glucagon
Acts primarily on liver cells.
Detected by receptors on surface of liver cells.
Stimulates glycogen breakdown & inhibits glycogenesis.
Glucagon also blocks glycolysis & stimulates
gluconeogenesis.
Epinephrine
Low levels of glucose induce release of Epinephrine
Acts primarily on skeletal muscle.
Detected by receptors at surface of cells.
Stimulates glycogen breakdown & inhibits glycogenesis.
Glucagon and epinephrine both stimulate intracellular pathway via increasing
levels of cAMP
Insulin
High levels of glucose induce release of insulin from β-
cells of islets of Langerhan in the pancreas.
Detected by receptors at surface of muscle and liver
cells.
Increases glycogenesis in muscle.
Intracellular signal pathway involvescomplex sequential phosphorylations
and dephosphorylations
Epinephrine and glucagon inhibit glycogen synthesis
1. protein kinase A phosphorylates glycogen synthase, decreasing its activity.
How is Glycogenesis Inhibited?
2. also phosphorylase kinase can phosphorylate glycogen synthase, inactivating it.
Complex process stimulated by Insulin
dephosphorylation is the major pathway for stimulation of
glycogenesis in liver and resting muscles
Insulin indirectly activates a phosphoprotein phosphatase:
How is Glycogenesis Activated?
glycogen synthase b glycogen synthase a
phosphorylated dephosphorylated
less active active
Differences between liver glycogen
and muscle glycogen
Muscle glycogenLiver glycogen
Blood glucose only 1. Blood glucose:
2. Other hexoses
3. Non-CHO sources
Source
400 grams maximum120 grams maximumAmount
1%6%Concentration
Private source of energy for
muscles only
General store of glucose for all body
cells
Functions
Lactate (due to the absence of
G6Pase)
Glucose End product
Same
Same
No effect
Stimulate glycogenesis
Stimulate glycogenolysis
Stimulate glycogenolysis
Effect of hormones
1. Insulin
2. Epinephrine
3. Glucagon